Journal of Neurogastroenterology and Motility 2019; 25(2): 332-333  https://doi.org/10.5056/jnm19010
Effect of Mizagliflozin on Postprandial Plasma Glucose in Patients With Functional Constipation
Shin Fukudo1,2, Kohei Kaku3
1Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan, 2Department of Psychosomatic Medicine, Tohoku University Hospital, Sendai, Japan, 3Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
Published online: April 30, 2019.
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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TO THE EDITOR: We read the recent review by Fukui et al1 in this journal. In their paper, they referred that the bacterial product short chain fatty acid promotes glucose regulating hormones including glucagon-like peptide 1.1 We consider their review to be accurate and to provide further insight to the following phenomena.

Mizagliflozin, a novel sodium-glucose cotransporter 1 inhibitor, suppresses the absorption of glucose and water in the intestine.2,3 We reported that mizagliflozin showed favourable efficacy and safety for patients with functional constipation and the risk of hypoglycaemia would be low.4 However, the dynamic data of postprandial plasma glucose under the administration of mizagliflozin has not been shown yet.

A randomised open-label study which evaluated the effects of oral administration of mizagliflozin 5 mg or 10 mg once daily at 30 minutes after breakfast for 2 weeks on plasma glucose and spontaneous bowel movement in patients with functional constipation was conducted in Japan (ClinicalTrials.gov NCT02343978). Twenty five patients (5 mg, n = 13 and 10 mg, n = 12) were enrolled in the study. After 2-weeks, postprandial plasma glucose and insulin at 1 hour and 2 hours in 10 mg of mizagliflozin and insulin at 2 hours in 5 mg of mizagliflozin were significantly lower than those in the baseline (Table). Areas under the curves for plasma glucose and insulin were not changed by 5 mg but significantly reduced by 10 mg of mizagliflozin (glucose, P = 0.043 and insulin, P = 0.007, one-sample t test). No hypoglycemic symptoms were induced by mizagliflozin but one patient showed hypoglycemic value (58 mg/dL) of postprandial plasma glucose at 2 hours in 10 mg of mizagliflozin. The mean number of spontaneous bowel movement per week significantly increased from 2.13 (SD, 0.45) at baseline to 7.99 (9.35) at week 2 in the 5 mg group and from 1.76 (0.62) to 6.81 (4.94) in the 10 mg group.

These results suggest that mizagliflozin actually inhibits postprandial glucose absorption from the intestine and has insulin-sparing effect. As Spiller5 previously commented, altered microbiota by the luminal glucose is one of factors affecting the effect of mizagliflozin. Therefore, this study provides another evidence of the review by Fukui et al.1 This study also supports the concept of low risk of hypoglycemia by sodium-glucose cotransporter 1 inhibitors6, but low value of plasma glucose in rare cases should be recognized for further clinical studies.

Tables

Changes in Plasma Glucose and Insulin Levels in the Meal Tolerance Test in the 5 mg and 10 mg Group

Group Weeks Item Times (hr) n Mean SD Min Q1 Median Q3 Max P-value (week 0 vs 2)
Plasma glucose (mg/dL)
 Mizagliflozin 5 mg 0 FPG 0 13 94.2 11.1 79 87 92 100 114 -
PPG 0.5 13 141.8 18.7 111 133 141 151 175 -
1 13 139.2 41.9 88 104 131 165 219 -
2 13 105.0 36.4 72 86 90 108 208 -
2 FPG 0 13 95.1 13.0 77 87 91 101 124 0.665
PPG 0.5 13 140.3 32.0 109 116 135 156 210 0.797
1 13 125.8 48.2 81 98 110 129 231 0.216
2 13 91.0 20.3 71 78 87 89 134 0.064
 Mizagliflozin 10 mg 0 FPG 0 12 92.6 10.0 79 88 92 96 118 -
PPG 0.5 12 143.4 31.0 107 121 141 150 206 -
1 12 129.0 45.0 81 100 109 154 243 -
2 12 105.8 28.5 76 84 100 124 163 -
2 FPG 0 12 93.4 7.2 83 89 93 97 111 0.659
PPG 0.5 12 144.6 20.4 105 127 147 159 177 0.839
1 12 110.0 26.8 72 92 98 132 156 0.044
2 12 82.6 14.6 58 76 83 91 105 0.009
Insulin (μU/mL)
 Mizagliflozin 5 mg 0 Fasting 0 13 5.28 2.24 2.7 3.8 4.9 5.6 10.1 -
After meal 0.5 13 65.41 32.58 28.4 40.2 54.8 96.2 119.5 -
1 13 58.07 25.60 18.8 40.8 49.5 70.9 105.8 -
2 13 41.22 23.28 15.1 20.8 36.6 56.8 87.9 -
2 Fasting 0 13 5.75 3.09 1.8 3.7 5.5 6.6 11.1 0·519
After meal 0.5 13 68.16 31.28 22.7 46.6 63.9 89.0 121.3 0·504
1 13 53.07 27.98 24.7 28.1 37.2 72.5 111.5 0·577
2 13 13.62 8.16 4.5 7.0 10.6 19.6 32.6 < 0.001
 Mizagliflozin 10 mg 0 Fasting 0 12 5.23 3.03 1.2 3.4 4.2 7.1 11.2 -
After meal 0.5 12 79.03 74.08 21.8 37.5 58.1 93.6 296.0 -
1 12 56.49 28.44 31.5 39.3 44.4 68.4 130.3 -
2 12 35.34 12.58 18.1 23.3 36.5 45.5 57.7 -
2 Fasting 0 12 4.89 1.77 3.2 3.9 4.5 5.2 9.9 0.634
After meal 0.5 12 72.98 50.39 32.2 39.2 55.4 77.7 190.7 0.582
1 12 39.88 17.11 18.8 21.6 39.9 55.1 64.9 0.021
2 12 8.92 2.85 5.0 6.7 8.0 12.0 13.5 < 0.001

Min, minimum; Q, quartile; Max, maximum; FPG, fasting plasma glucose; PPG, postprandial plasma glucose.

At week 0 (without mizagliflozin) and 2 (with mizagliflozin), blood glucose and insulin levels were measured at 0, 30, 60, and 120 minutes after the patients ingested 431 kcal standard breakfast of 67.2 g to 68.5 g of carbohydrates, 5.4 g to 5.6 g of fat, and 19.7 g to 21.1 g of protein.

P-values were calculated using the one-sample t test.


Footnotes

Financial support: This study was funded by Kissei Pharmaceutical Co, Ltd (Grant No. KWA1205).

Conflicts of interest: Shin Fukudo reports grants and personal fees from Kissei Pharmaceutical, during the conduct of the study; personal fees from Dainippon Sumitomo Pharma, grants and personal fees from Abott Japan, personal fees from Scampo Pharma, grants from Ono Pharmaceutical, grants and personal fees from Astellas Pharmaceutical, personal fees from Sanwa Chemical Co. Ltd, personal fees from Zeria, personal fees from Glaxo-Smith-Kline, personal fees from Mochida Pharmaceutical, personal fees from Shionogi Pharmaceutical, grants and personal fees from AstraZeneca, grants from Smoking Research Foundation, grants and personal fees from Tsumuta Co. Ltd., personal fees and non-financial support from Miyarisan Pharmaceutical, grants from Kao Co. Ltd., and grants from Zespri Co. Ltd, outside the submitted work. Kohei Kaku reports personal fees from Kissei Pharmaceutical, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants from Daiichi Sankyo, grants and personal fees from Taisho Toyama Pharmaceutical, grants and personal fees from Mitsubishi Tanabe Pharma, grants and personal fees from Takeda Pharmaceutical, grants and personal fees from Astellas Pharma, personal fees from AstraZeneca, personal fees from Sumitomo Dainippon Pharma, personal fees from Kissei Pharmaceutical, personal fees from Kowa, personal fees from MSD, personal fees from Novartis Pharma, personal fees from Ono Pharmaceutical, and personal fees from Sanofi K.K, outside the submitted work.

Author contributions: Shin Fukudo and Kohei Kaku designed, performed, and analysed the study. All authors contributed to data interpretation, writing, and final approval of the manuscript.

References
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